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Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia. Rodent models of mIA have explored possible mechanisms underlying this paradigm and provide a vital tool for preclinical research. However, a comprehensive analysis of the molecular changes that occur in mIA-models is lacking, hindering identification of robust clinical targets. This systematic review assesses mIA-driven transcriptomic and epigenomic alterations in specific offspring brain regions. Across 118 studies, we focus on 88 candidate genes and show replicated changes in expression in critical functional areas, including elevated inflammatory markers, and reduced myelin and GABAergic signalling proteins. Further, disturbed epigenetic markers at nine of these genes support mIA-driven epigenetic modulation of transcription. Overall, our results demonstrate that current outcome measures have direct relevance for the hypothesised pathology of schizophrenia and emphasise the importance of mIA-models in contributing to the understanding of biological pathways impacted by mIA and the discovery of new drug targets.

Treatment of major depressive disorder (MDD) including treatment-resistant depression (TRD) remains a major unmet need. Although there are several classes of dissimilar antidepressant drugs approved for MDD, the current drugs have either limited efficacy or are associated with undesirable side effects and withdrawal symptoms. The efficacy and side effects of antidepressant drugs are mainly attributed to their actions on different monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). Development of new antidepressants with novel targets beyond the monoamine pathways may fill the unmet need in treatment of MDD and TRD. The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.

Women with premenstrual dysphoric disorder (PMDD) appear to have altered central nervous system sensitivity to neuroactive steroid hormones, manifesting as affective symptoms and heightened arousal in the luteal phase of the menstrual cycle. In particular, women with PMDD appear less sensitive to allopregnanolone, a positive allosteric GABA-A receptor (GABA-A-R) modulator. This study evaluated psychophysiologic reactivity in women with PMDD in the follicular and luteal phases of the menstrual cycle, utilizing anxiety-potentiated startle (APS), a potential translational marker of GABA-A-R sensitivity. The study also assessed APS response to low-dose sertraline treatment in women with PMDD. Participants’ APS and fear-potentiated startle (FPS) were assessed in the follicular and luteal phases. Women with PMDD received 50 mg sertraline in the following luteal phase to examine impact on APS and FPS. There were no significant differences between controls (n = 41) and PMDD participants (n = 36) in change from follicular to luteal phases in baseline startle, APS nor FPS. However, among participants who responded to sertraline, APS was higher in the untreated luteal phase than the follicular phase, but lower in the treated luteal phase than the follicular phase. These data demonstrate elevated psychophysiologic arousal in the luteal phase among some women with PMDD, suggesting impaired ability to modulate arousal reactivity. Specifically, alterations in APS suggest potential GABA-A-R changes across the menstrual cycle and in response to sertraline among treatment responders.

Background: Dose reduction of antipsychotic maintenance treatment in individuals with schizophrenia could be desirable to minimise adverse effects, but evidence for this strategy is unclear. We aimed to compare risks and benefits of reduced versus standard doses of antipsychotics. Methods: We searched Embase, Medline, PsycINFO, and the Cochrane Library from database inception until June 17, 2020, for randomised trials in adults with schizophrenia or schizoaffective disorder lasting at least 24 weeks, including individuals clinically stable at baseline, and comparing at least two doses of the same antipsychotic, excluding trials in first-episode psychosis or treatment-resistant schizophrenia. We compared low-dose (within 50–99% of the lower limit of the standard dose) and very-low dose (less than 50% of the lower limit) with standard dose, defined as doses higher than the lower limit of the treatment dose recommended by the International Consensus Study. Data from published reports on number of participants, treatment, sex, age, number of events, and changes in psychopathology scores were extracted independently by at least two authors. Investigators or sponsors were contacted by email to obtain missing information regarding outcomes. Co-primary outcomes were relapse and all-cause discontinuation. Study-level data were meta-analysed using random-effects models, calculating risk ratios (RRs) for dichotomous data, and Hedges' g for continuous data. The protocol was registered with OSF registries. Findings: 7853 references were identified in the database search and one additional reference from a manual review of relevant studies. 5744 abstracts were assessed for eligibility, and 101 references were assessed for full-text review. Of these, 79 were excluded for a variety of reasons, resulting in 22 studies being included in the meta-analysis, reporting on 24 trials and 3282 individuals. Study participants had a median age of 38 years (IQR 36–40) with 2166 (65·9%) males and 1116 (34·0%) females. Compared with standard dose, low dose increased the risk of relapse by 44% (16 trials, 1920 participants; RR 1·44, 95% CI 1·10–1·87; p=0·0076; I 2=46%) and the risk of all-cause discontinuation by 12% (16 trials, 1932 participants; RR 1·12, 1·03–1·22; p=0·0085; I 2=0%). Very low dose increased the risk of relapse by 72% (13 trials, 2058 participants; RR 1·72, 95% CI 1·29–2·29; p=0·0002; I 2=70%) and all-cause discontinuation by 31% (11 trials, 1866 participants; RR 1·31, 1·11–1·54; p=0·0011; I 2=63%). Compared with low dose, very low dose did not significantly increase the risk of relapse (five trials, 686 participants; RR 1·31, 95% CI 0·96–1·79; p=0·092; I 2=51%) or all-cause discontinuation (five trials 686 participants; RR 1·11, 95% CI 0·95–1·30; p=0·18; I 2=43%). Subgroup analyses comparing double-blind versus open-label studies, first-generation versus second-generation antipsychotics, and oral versus long-acting injectable antipsychotics were consistent with the overall results. Most studies were classified as having some concerns in the risk of bias assessment, which was mainly caused by absence of publicly available study registrations. Interpretation: During maintenance treatment in multi-episode schizophrenia, antipsychotic doses should probably not be reduced below the standard dose range recommended for acute stabilisation, because reducing the dose further is associated with an increased risk of both relapse and all-cause discontinuation. Funding: None

Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD.The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures.The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference -18%; 95% CI=-29, -8). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference).If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.

Background: Little research to date has investigated the spectrum of bladder health in women, including both bladder function and well-being. Therefore, we expanded our previous baseline analysis of bladder health in the Boston Area Community Health (BACH) Survey to incorporate several additional measures of bladder-related well-being collected at the 5-year follow-up interview, including one developed specifically for women. Methods: At follow-up, participants reported their frequency of 15 lower urinary tract symptoms (LUTS), degree of life impact from and thought related to urinary symptoms or pelvic/bladder pain/discomfort, and perception of their bladder condition. Prevalence ratios were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. The BACH Survey was approved by the New England Research Institutes Institutional Review Board and all participants provided written informed consent. Results: Generally similar findings were observed in the 5-year cross-sectional analysis as at baseline, irrespective of how we categorized LUTS or measured bladder-related well-being. Approximately one in five women (16.2%–18.0% of 2527 eligible women) reported no LUTS and no diminished bladder-related well-being, the majority (55.8%–65.7%) reported some LUTS and/or diminished well-being, and a further one in five (16.9%–26.6%) reported the maximum frequency, number, or degree of LUTS and/or diminished well-being. Measures of storage function (urinating again after

Background The increased use of Mohs micrographic surgery (MMS) to treat melanoma has been accompanied by wide variations in practice patterns and a lack of best practice guidelines. Objective The present study was a nationwide cross-sectional survey of Mohs surgeons to elucidate commonalities and variations in their use of MMS to treat melanoma. Materials and methods A cross-sectional analysis was performed using survey responses of Mohs surgeons with membership in the American College of Mohs Surgery. Results A total of 210/513 (40.9%) participants used MMS to treat melanoma of any subtype and 123/210 (58.6%) participants within this group treated invasive T1 melanoma (AJCC Eighth Edition) with MMS. A total of 172/210 (81.9%) participants debulked melanoma in situ (MIS). Average margin size of the first Mohs stage for MIS was 4.96 ± 1.74 mm. A total of 149/210 (71.0%) participants used immunohistochemical stains, with 145/149 (97.3%) using melanoma antigen recognized by T-cells 1 (MART-1) in 96.5% of melanoma cases treated with MMS. Conclusion Over half of surveyed Mohs surgeons treating melanoma with MMS are treating early invasive melanoma with MMS. Most Mohs surgeons treating melanoma with MMS debulk MIS and virtually all use MART-1 when excising invasive melanoma with MMS.

Introduction and objectives: Cognitive impairment associated with schizophrenia (CIAS) greatly reduces patients’ functionality, and remains an unmet clinical need. The sub-chronic phencyclidine (scPCP) rat model is commonly employed in studying CIAS. We have previously shown that voluntary exercise reverses impairments in novel object recognition (NOR) induced by scPCP. However, there has not been a longitudinal study investigating the potential protective effects of exercise in a model of CIAS. This study aimed to investigate the pro-cognitive and protective effects of exercise on CIAS using the translational NOR and attentional set-shifting tasks (ASST). Methods: Female Lister Hooded rats were either exercised (wheel running for one hour per day, five days per week, for six weeks; n=20) or not ( n=20) and then tested in a natural-forgetting NOR test. Rats in each group were then administered either PCP (2 mg/kg intraperitoneally (i.p.)) or saline solution (1 mL/kg i.p.) for seven days, followed by seven days washout. Three NOR tests were conducted immediately and two and nine weeks after washout, and a natural-forgetting NOR test was carried out again eight weeks post washout. Rats were trained and tested in ASST from week 6 to week 10 post washout. Results: Non-exercised rats displayed a deficit in both of the natural-forgetting NOR tests, whereas exercised rats did not. The scPCP exercise group did not show the expected deficit in NOR at any time point, and had a significantly ameliorated deficit in the ASST compared to the scPCP control group. Conclusion: Voluntary exercise has long-lasting pro-cognitive and protective effects in two cognitive domains. Exercise improves cognition and could provide protection against CIAS.

Whether a major depressive episode occurring in the postpartum period (i.e., postpartum depression [PPD]) is sufficiently distinct from major depressive episodes occurring at other times (i.e., major depressive disorder) to warrant a separate diagnosis is a point of debate with substantial clinical significance. The evidence for and against diagnostic distinction for PPD is reviewed with respect to epidemiology, etiology, and treatment. Overall, evidence that PPD is distinct from major depressive disorder is mixed and is largely affected by how the postpartum period is defined. For depression occurring in the early postpartum period (variably defined, but typically with onset in the first 8 weeks), symptom severity, heritability, and epigenetic data suggest that PPD may be distinct, whereas depression occurring in the later postpartum period may be more similar to major depressive disorder occurring outside of the perinatal period. The clinical significance of this debate is considerable given that PPD, the most common complication of childbirth, is associated with immediate and enduring adverse effects on maternal and offspring morbidity and mortality. Future research investigating the distinctiveness of PPD from major depressive disorder in general should focus on the early postpartum period when the rapid decline in hormones contributes to a withdrawal state, requiring profound adjustments in central nervous system function.

Objective To characterize the influence of early life stress on peripheral basal inflammatory markers across the menopause transition. Methods Participants from the longitudinal Penn Ovarian Aging study were assessed for childhood adversity at study end (14 years) using the Adverse Childhood Experiences (ACE) questionnaire. Responses were categorized as low (0–1) or high (≥2) ACE exposure. The stored blood sample catalogue was reviewed to exclude those samples collected during use of medications that could impact immune status or medications suggestive of infection or allergies. Remaining blood samples (n ​= ​640) from 167 participants were assayed for interleukin-6 (IL-6), interleukin 1-beta (IL-1β), high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor alpha (TNF-α). Menopause staging (premenopause, early transition, late transition, and postmenopause) was determined by questionnaire and menstrual diaries at yearly assessments. Generalized linear models for repeated measures were used to quantify the association between outcomes of interest (i.e., IL-6, IL-1β, hsCRP, and TNF-α) and exposures (i.e., menopause stage, ACE status, their interaction) while controlling for relevant covariates (i.e., BMI, smoking, age at first blood sample, and race). Inflammatory marker levels were log-transformed for modeling. Results Log IL-6 levels were higher in the late perimenopause versus premenopause (p ​= ​0.035). Menopause stage ​× ​ACE interaction was observed for log IL-6, IL-1β, and TNF-α (p ​= ​0.042, p ​= ​0.054, p ​= ​0.053, respectively); for individuals with high (≥2) ACE exposure, IL-6 was higher in the late perimenopause (p ​= ​0.015) while IL-1β and TNF-α were lower in the postmenopause versus premenopause (p ​= ​0.019 and p ​= ​0.020). Conclusions Results from this investigation indicate that the late perimenopause stage may be a window of risk for inflammation, particularly for individuals with greater childhood adversity. Prospective studies designed to address childhood stress and inflammation across the menopause transition are needed to confirm these findings. Heightened inflammation, even if transitory, may have negative impact on healthy aging., Highlights • Inflammatory marker fluctuations were related to menopause stage. • Log IL-6 and TNF-α levels were higher in late peri-than premenopause. • Menopause stage and ACEs interacted to impact inflammatory markers. • Log IL-6, IL-1β, and TNF-α were higher in late peri-than premenopause for high ACE. • These data were adjusted for smoking, body mass index, age, and race.

Susceptibility and resilience to stress depend on 1) the timing of the exposure with respect to development, 2) the time across the life span at which effects are measured, and 3) the behavioral or biological phenotype under consideration. This translational review examines preclinical stress models that provide clues to causal mechanisms and their relationship to the more complex phenomenon of stress-related psychiatric and cognitive disorders in humans. We examine how genetic sex and epigenetic regulation of hormones contribute to the proximal and distal effects of stress at different epochs of life. Stress during the prenatal period and early postnatal life puts male offspring at risk of developing diseases involving socialization, such as autism spectrum disorder, and attention and cognition, such as attention-deficit/hyperactivity disorder. While female offspring show resilience to some of the proximal effects of prenatal and early postnatal stress, there is evidence that risk associated with developmental insults is unmasked in female offspring following periods of hormonal activation and flux, including puberty, pregnancy, and perimenopause. Likewise, stress exposures during puberty have stronger proximal effects on girls, including an increased risk of developing mood-related and stress-related illnesses, such as depression, anxiety, and posttraumatic stress disorder. Hormonal changes during menopause and andropause impact the processes of memory and emotion in women and men, though women are preferentially at risk for dementia, and childhood adversity further impacts estradiol effects on neural function. We propose that studies to determine mechanisms for stress risk and resilience across the life span must consider the nature and timing of stress exposures as well as the sex of the organism under investigation.

Background In phase 3 trials of patients with resected high-risk renal cell carcinoma, adjuvant sunitinib has demonstrated no overall survival (OS) benefit, an uncertain disease-free survival (DFS) benefit, and increased toxicity versus placebo. To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer (ASSURE) trial. Methods The authors conducted a post hoc subgroup analysis of age and sex among patients in the ASSURE trial. Adjusted hazard ratios (HRs) for OS and DFS were evaluated with sunitinib or sorafenib versus placebo in 4 patient subgroups defined by sex and median age at the time of the study. Results Sunitinib treatment was associated with decreased OS (HR, 2.21; 95% confidence interval, 1.29-3.80) among women aged >56 years, but not in women aged ≤56 years or men of any age. Similar associations with age and sex were observed for DFS, but these were not statistically significant (women aged >56 years: HR, 1.41 [95% confidence interval, 0.94-2.10]). No such association was found for sorafenib. The interaction by age and sex on mortality was found to be statistically significant for sunitinib (P = .01), but not sorafenib (P = .10). Conclusions Adjuvant sunitinib may increase mortality among older women with renal cell carcinoma. Given the recent approval of adjuvant sunitinib for patients with high-risk resected renal cell carcinoma, additional studies are needed to confirm these findings.

During pregnancy, programming of the fetal central nervous system (CNS) establishes vulnerabilities for emergence of neuropsychiatric phenotypes later in life. Psychosocial influences during pregnancy, such as stressful life events or chronic stress, correlate with offspring neuropsychiatric disorders and with inflammation, respectively. Stress promotes inflammation, but the role of inflammation as a mediator between maternal psychosocial stress and offspring neuropsychiatric outcomes has not been extensively studied in humans. This review summarizes clinical evidence linking specific types of stress to maternal inflammatory load during pregnancy. We propose that inflammation is a mediator in the relationship between psychosocial stress and offspring neuropsychiatric outcomes, potentially influenced by poor maternal glucocorticoid-immune coordination. We present relevant experimental animal research supporting this hypothesis. We conclude that clinical and preclinical research support the premise that stress-induced maternal immune activation (MIA) contributes in part to prenatal programming of risk. Programming of risk is likely due to a combination of vulnerabilities, including multiple or repeated inflammatory events, timing of such events, poor maternal regulation of inflammation, genetic vulnerability, and lifestyle contributors.

Background Adverse childhood experiences (ACEs), such as abuse or chronic stress, program an exaggerated adult inflammatory response to stress. Emerging rodent research suggests that the gut microbiome may be a key mediator in the association between early life stress and dysregulated glucocorticoid-immune response. However, ACE impact on inflammatory response to stress, or on the gut microbiome, have not been studied in human pregnancy, when inflammation increases risk of poor outcomes. The aim of this study was to assess the relationships among ACE, the gut microbiome, and cytokine response to stress in pregnant women. Methods Physically and psychiatrically healthy adult pregnant women completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and gave a single stool sample between 20 and 26 weeks gestation. Stool DNA was isolated and 16S sequencing was performed. Three 24-hour food recalls were administered to assess dietary nutrient intake. A subset of women completed the Trier Social Stress Test (TSST) at 22–34 weeks gestation; plasma interleukin-6 (IL-6), interleukin-1β (IL-1β), high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), and cortisol were measured at four timepoints pre and post stressor, and area under the curve (AUC) was calculated. Results Forty-eight women completed the ACE-Q and provided stool; 19 women completed the TSST. Women reporting 2 or more ACEs (high ACE) had greater differential abundance of gut Prevotella than low ACE participants (q = 5.7 × 10^−13). Abundance of several gut taxa were significantly associated with cortisol, IL-6, TNF-α and CRP AUCs regardless of ACE status. IL-6 response to stress was buffered among high ACE women with high intake of docosahexaenoic acid (DHA) (p = 0.03) and eicosapentaenoic acid (EPA) (p = 0.05). Discussion Our findings suggest that multiple childhood adversities are associated with changes in gut microbiota composition during pregnancy, and such changes may contribute to altered inflammatory and glucocorticoid response to stress. While preliminary, this is the first study to demonstrate an association between gut microbiota and acute glucocorticoid-immune response to stress in a clinical sample. Finally, exploratory analyses suggested that high ACE women with high dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) had a dampened inflammatory response to acute stress, suggesting potentially protective effects of ω-3s in this high-risk population. Given the adverse effects of inflammation on pregnancy and the developing fetus, mechanisms by which childhood adversity influence the gut-brain axis and potential protective factors such as diet should be further explored.

Background Major depressive disorder (MDD) affects 10% of pregnancies. Because transcranial magnetic stimulation (TMS) is a nonmedication option, psychiatric patients who do not tolerate or prefer to avoid antidepressants are good candidates for TMS. Method In a randomized controlled trial of twenty-two women with MDD in the second or third trimester of pregnancy, subjects were randomized to active TMS (n=11) or sham TMS (n=11). This study took place at a single academic center. Subjects received 20 sessions of TMS to the right dorsolateral prefrontal cortex at 1 Hz as a single train of 900 pulses per session at 100% motor threshold. Estradiol and progesterone and were measured before session 1 and after session 20. Results Results demonstrated significantly decreased Hamilton Depression Rating Scale (HDRS-17) scores for the active compared to the sham group (p=0.003). Response rates were 81.82% for the active and 45.45% for the sham coil (p=0.088). Remission rates were 27.27% for the active 18.18% for the sham coil (p=0.613). Late preterm birth (PTB) occurred in three women receiving active TMS. All other maternal and delivery outcomes were normal. Conclusions Right-sided, low frequency TMS was effective in reducing depressive symptoms in this sample of pregnant women. There may be a possibility that TMS is associated with late PTB although a larger sample size would be needed for adequate power to detect a true difference between groups. This study demonstrated that TMS is low risk during pregnancy although larger trials would provide more information about the efficacy and safety of TMS in this population. This trial shows that an RCT of a biologic intervention in pregnant women with psychiatric illness can be conducted.

Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21

Summary Background Lower urinary tract symptoms (LUTS) are common in children and adolescents. Non-invasive tests evaluating bladder function are generally preferred over invasive tests, yet few studies have explored the range of normative values for these tests in healthy, asymptomatic children. Objective To define normative reference ranges for non-invasive tests of bladder function in healthy, asymptomatic girls and adolescents. Study design A comprehensive search strategy was performed in seven electronic databases through October 2019. English-language studies reporting data on voiding frequency, voided and postvoid residual volumes (PVR) and uroflowmetry results in healthy, asymptomatic girls (mean age ≥ 5 years) were included. Two independent reviewers performed study review, data extraction, and quality assessment. Overall mean estimates and 95% confidence intervals for each bladder function parameter were calculated using random effects models, and 95% normative reference values were estimated. Results Ten studies met eligibility criteria for the meta-analysis (n = 2143 girls, age range: 3–18). Mean estimates of maximum voided volume and PVR were 233.4 ml (95% CI 204.3–262.6; n = 1 study) and 8.6 ml (95% CI 4.8–12.4; n = 2 studies) respectively. Pooled mean estimates for uroflowmetry parameters were: 21.5 ml/s (95% CI 20.5–2.5) for maximum flow rate (n = 6 studies), 12.5 ml/s (95% CI 11.2–13.8) for mean flow rate (n = 6 studies), 6.8 s (95% CI 4.4–9.3) for time to maximum flow (n = 3 studies), 15.7 s (95% CI 13.0–18.5) for flow time (n = 3 studies), and 198.7 ml (95% CI 154.2–234.2) for voided volume (n = 9 studies). No studies reported estimates of voiding frequency. Between-study heterogeneity was high (89.0–99.6%). Conclusions Although we were able to calculate pooled mean estimates for several parameters, the small number of included studies and the wide age ranges of participants preclude generalization of reference values to all healthy girls. Further research is needed to determine normative reference values within specific age groups.

Background Direct oral anticoagulants (DOACs), such as apixaban, rivaroxaban, and dabigatran, are increasingly being used to provide prophylaxis and treatment for arterial and venous thromboembolism. Multiple procedural subspecialties have implemented guidelines detailing time frames for perioperative DOAC interruption; however, the impact of perioperative DOAC interruption in patients undergoing dermatologic surgery is currently unknown, and evidence-based guidelines are lacking. Objective To assess the 30-day postoperative rate of thrombotic complications (ischemic stroke, transient ischemic attack, systemic embolism, deep vein thrombosis [DVT] and pulmonary embolism) in patients with nonvalvular atrial fibrillation (AF) or a history of DVT who underwent perioperative DOAC interruption during dermatologic surgery. Methods A retrospective medical record review was performed of all patients with AF or a history of DVT who underwent perioperative DOAC interruption during dermatologic surgery at Advanced Dermatologic Surgery and the University of Kansas Medical Center between January 1, 2016, and August 31, 2020. Results Among 806 operations, comprising 750 Mohs micrographic operations (93.1%) and 56 excisions (6.9%), 1 patient (0.14% of patients with AF) sustained a transient ischemic attack and 2 patients (0.25% of all patients) sustained minor bleeding complications during the 30-day postoperative period. Conclusion Perioperative DOAC interruption appears to be safe and efficacious in dermatologic surgery.

Objective Our study aimed to examine psychiatric diagnoses and treatment preceding a schizophrenia diagnosis in adolescents, stratified by sex and race/ethnicity. Methods Using Medicaid physical and behavioral health and pharmacy claims data, we identified 1,459 adolescents who were aged 9-17 years and diagnosed with schizophrenia between January 2006 through June 2009. Psychiatric diagnosis, mental health service use including psychiatric hospitalization, residential treatment and outpatient therapy and psychotropic medication use preceding schizophrenia were identified. Results Forty-five percent of the adolescents were diagnosed with one or more psychiatric conditions. More than 40% of the adolescents were hospitalized or placed in a residential treatment facility for other psychiatric conditions preceding schizophrenia. Overall, 72% of the adolescents were prescribed with one or more psychotropic medications and 22% were prescribed with three or more psychotropic medications in the year prior to their first schizophrenia diagnosis. We found that sex and race/ethnicity influence preceding psychiatric conditions and psychiatric treatment use. Conclusions Careful screening and evaluation to validate diagnoses is important as the presence of certain psychiatric morbidity is common among adolescents with schizophrenia during the prodromal period. Developing acceptable and accessible interventions that will reduce psychiatric hospitalization and residential treatment care and improve care connection for schizophrenia treatment is important to mitigate complexity in treatment for adolescents and reduce cost burden for families and the society. Integrating health claims data in the development of schizophrenia risk conversion models can be useful in effectively predicting ideal timing of tailored interventions for adolescents with preceding psychiatric conditions.

Epidemiological, clinical, and basic research over the past thirty years have described the benefits of estrogen on cognition, mood, and brain health. Less is known about tamoxifen, a selective estrogen receptor modifier (SERM) commonly used in breast cancer which is able to cross the blood-brain barrier. In this article, we review the basic pharmacology of tamoxifenas well as its effects on cognition and mood. The literature reveals an overall impairing effect of tamoxifen on cognition in breast cancer patients, hinting at central antiestrogen activity. On the other hand, tamoxifen demonstrates promising effects in psychiatric disorders, like bipolar disorder, where its therapeutic action may be independent of interaction with estrogen receptors. Understanding the neuropsychiatric properties of SERMs like tamoxifen can guide future research to ameliorate unwanted side-effects and provide novel options for difficult to treat disorders.

AIMS To determine whether childhood adversity is associated with self-reported lower urinary tract symptoms (LUTS) among older adult women. METHODS A convenience sample of women (≥55 years old) who presented to an academic urology practice or who had participated in a previous bladder health prevention study completed questionnaires including the LUTS Tool (on frequency and bother of LUTS), the Adverse Childhood Experiences (ACEs) Questionnaire, the Spielberger State-Trait Anxiety Inventory, and the Center for Epidemiologic Studies Depression Scale. RESULTS The average age (SD) of participants (N = 151) was 64.7 (6.9) years. The total number of ACEs predicted the total number of LUTS, β = .39 (95% confidence interval [CI] = 0.14, 0.64), P = .003, as well as LUTS frequency, β = .09 (95% CI = 0.04, 0.13), P

Endocrine organizational and activational influences on cognitive and affective circuits are likely critical to the development of premenstrual dysphoric disorder (PMDD), a sex-specific hormone-dependent mood disorder. An overview of the anatomical and functional neural characterization of this disorder is presented here by means of neuroimaging correlates, identified from eighteen publications (n = 361 subjects). While white matter integrity remains uninvestigated, greater cerebellar grey matter volume and metabolism were observed in patients with PMDD, along with altered serotonergic and GABAergic neurotransmission. Differential corticolimbic activation in response to emotional stimuli distinguishes the PMDD brain, namely enhanced amygdalar and diminished fronto-cortical function. Thus far, the emotional distress and dysregulation linked to PMDD seem to be defined by structural, chemical and functional brain signatures; however, their characterization remains sparsely studied and somewhat inconsistent. Clear and well-replicated neurobiological features of PMDD are needed to promote timely diagnoses and inform development of prevention and treatment strategies.

Objective: To quantify the economic burden of postpartum depression (PPD) that accrues to commercially insured households in the year following childbirth. Methods: Administrative claims data from OptumHealth Care Solutions (2009-2016) were used to identify households that included women identified with PPD per the algorithm and propensity score–matched comparison households of women who were not identified with PPD or a history of depression after childbirth. Study outcomes included direct total all-cause medical and pharmaceutical costs during the first year following childbirth and number of outpatient visits at the household level stratified by household member. Results: Households affected by PPD as identified by the algorithm (N = 7,769) incurred 22% higher mean total all-cause medical and pharmaceutical spending than unaffected matched controls (N = 41,308) during the first year following childbirth ($36,049 versus $29,448, P 50%) of total all-cause spending. Mothers identified with PPD had significantly higher annual mean direct total all-cause medical and pharmaceutical spending than their matched controls without PPD ($19,611 versus $15,410, P Conclusions: Households affected by PPD as identified by the algorithm incurred higher mean total all-cause medical and pharmaceutical spending during the first year following childbirth than did their matched controls identified without PPD, but not all costs were attributable to maternal treatment for PPD. These findings contribute to a better understanding of the potential economic burden associated with PPD and demonstrated costs may extend beyond the mother to members of the household.

Primary closure of suborbital skin defects can cause tension along the closure resulting in ectropion. The bicycle wheel analogy is a simple yet effective guide to aid in reducing tension vectors resulting in ectropion.

Keratoacanthomas are rapidly growing neoplasms of squamous epithelium. Despite their benign nature, they are often difficult to distinguish from squamous cell carcinoma and require excision. In cases in which excision is not successful or not desired, intralesional treatments may be considered. However, limited research exists on individual therapeutic efficacy. We present a 68-year-old man who developed multiple eruptive keratoacanthomas around the wound edge of a previous keratoacanthoma excision. Considering previous excisional failure, intralesional 5-fluorouracil was used as a treatment modality. Injections every 3-4 weeks over a course of 12 weeks induced clinical keratoacanthoma clearance with excellent cosmetic results. This case showcases that weekly intralesional 5-fluorouracil injections, as was the standard mode of treatment in previous case reports, may not be necessary. This less frequent injection strategy is more convenient for the patient and may lead to fewer treatments and less medication necessary. Although a case-by-case basis is needed for any alternative approach to keratoacanthoma treatment, this report is useful for the practicing clinician in showing that 5-fluorouracil may be efficacious in these difficult-to-treat patients.

Negative and cognitive deficit symptoms in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of cognitive dysfunction in the illness is urgently required to enhance the development of new improved therapeutic strategies. Careful validation of animal models that mimic the behaviour and pathology of complex psychiatric disorders is an essential step towards this goal. Non-competitive NMDAR (N-Methyl-d-aspartate receptor) antagonists e.g. phencyclidine (PCP), ketamine and dizocilpine (MK-801) can effectively replicate certain aspects of negative and cognitive deficits associated with schizophrenia in animals. In 2010 we reviewed the effects of NMDAR antagonism in tests for domains of cognition affected in schizophrenia, social behaviour and neuropathology, and in 2014, in tests for negative symptoms. In this update, we evaluate the most recent pharmacological strategies for restoring cognition in schizophrenia using NMDAR antagonist models, published since our original review in 2010 (cited over 225 times, excluding self-citations). Tests reviewed are, novel object recognition for visual recognition memory, attentional set shifting for executive function, and operant tests incorporating recent touchscreen technology for a range of domains including working memory, problem solving and attention, all impaired in schizophrenia. Moreover, we include an update on parvalbumin (PV)-expressing GABAergic interneurons and review, for the first time, the effects of NMDAR antagonists on gamma oscillations, circuitry integral for effective cognition. Data summarized in this review strongly confirm the reliability and usefulness of NMDAR antagonist animal models for evaluating novel therapeutic candidates, and for improving our understanding of the pathophysiology of cognitive deficits in schizophrenia. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female “characteristics” in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.

Objectives:This study sought to identify whether pregnancy complications differ between women with and without a psychiatric disorder diagnosis prior to pregnancy.Methods:Women who gave birth between 2007 and 2009 in Pennsylvania and were enrolled in Medicaid from one year prior to their pregnancy until their delivery were included (N=9,930); those with psychiatric disorders were compared with a matched control group (N=4,965 for each). Logistic regression analysis estimated the odds of having a pregnancy complication among those with a psychiatric diagnosis prior to pregnancy, adjusting for demographic characteristics and chronic general medical conditions.Results:Compared with the control group, women with a psychiatric disorder prior to pregnancy had greater odds of having at least one pregnancy complication (odds ratio=1.48, 95% confidence interval=1.37–1.61). Compared with the control group, their odds of antepartum hemorrhage were 1.50 times higher, their odds of preterm labor were 1.45 times higher...

Translation of women's mental health research has yet to impact overall prevalence and burden of Mood Disorders in the United States. The lack of standard measures and methodological coordination across studies has contributed to the slow impact of research on outcomes. The primary aims of this project were to demonstrate the process by which multiple investigators, sites, and settings administered a standard women's mental health questionnaire within a new Women's Depression Network. Information on the prevalence of mental health and service use across sites is provided.A standard women's mental health questionnaire was developed and administered across seven different women's health sites in the United States. Validated measures of depression and anxiety were included (Patient Health Questionnaire Depression Scale [PHQ-9] and Generalized Anxiety Disorder Scale [GAD-7]). Administration of the questionnaire was embedded into existing clinical or research activities at each site.Data from 1,316 women were collected from seven sites over 12 months. A total of 14% and 15% of the women scored at or above the cutoff on the PHQ-9 and GAD-7 respectively. Just over half of the women screening positive for either depression or anxiety reported current treatment use.Findings suggest that coordination and administration of a standard women's mental health questionnaire is feasible across multiple settings and sites. Results highlight a low percentage of treatment use across various settings. The infrastructure developed for this study sets the stage for hypothesis-driven studies that can facilitate coordinated, network-based research that has the potential to accelerate advances in the field.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of the same condition defined by its widespread skin and mucosal loss.1 SJS/TEN represents a true dermatologic emergency, as the disease quickly evolves and is often fatal without early identification and treatment. It is essential for all clinicians to be familiar with common signs associated with SJS/TEN, as patients are more likely to present initially to primary care providers and emergency physicians than they are to a dermatologist. Certain characteristics of SJS/TEN allow it to be distinguished from common mimickers such as Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), Erythema Multiforme (EM), and morbilliform drug reactions.1 We present the “SJS/TENN” mnemonic of clinical char acteristics to aid in the early diagnosis for suspected cases (Table 1). Table 1 Prevalence of clinical findings included in SJS/TENN mnemonic.

Objective This study compared psychiatric treatment discontinuation rates among pregnant women using psychotropic medications, outpatient psychotherapy, or both before conception. Methods Using data from Pennsylvania Medicaid Fee-For-Service and Managed Care Organization claims and Medicaid enrollment, 3030 women were identified who gave birth between 2007 and 2009, had ≥ 1 claim for psychiatric treatment during the 120 days prior to pregnancy, and were enrolled in Medicaid until they delivered. Kaplan–Meier and Cox regression analyses were used to estimate psychiatric treatment dropout rate during pregnancy and examine relationships between treatment dropout and age, race/ethnicity, and pre-pregnancy psychiatric diagnosis and treatment pattern. Results After the first trimester, the probability of discontinuing psychotropic medications was 83 versus 37.8% for cessation of psychotherapy among combined treatment users. Two or more psychotherapy sessions in the 4 months prior to pregnancy were associated with decreased psychotherapy dropout during pregnancy. Psychotherapy during pregnancy was associated with prenatal psychotropic medication adherence. Conclusions To retain women in treatment during pregnancy, when discontinuation from care is common, innovative models of care should consider type of pre-pregnancy mental healthcare and individual characteristics.

Summary Background Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABA A ) receptors, for the treatment of post-partum depression. Methods For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. Findings This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference −12·2, 95% CI −20·77 to −3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). Interpretation In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABA A receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. Funding Sage Therapeutics, Inc.

Background Right ventricular failure (RVF) complicates 9% to 44% of left ventricular assist device (LVAD) implants post-operatively. Current prediction scores perform only modestly in validation studies, and do not include immune markers. Chemokines are inflammatory signaling molecules with a fundamental role in cardiac physiology and stress adaptation. In this study we investigated chemokine receptor regulation in LVAD recipients who develop RVF. Methods Expression of chemokine receptor (CCR) genes 3 to 8 were examined in the peripheral blood of 111 LVAD patients, collected 24 hours before implant. RNA was isolated using a PAXgene protocol. Gene expression was assessed using a targeted microarray (RT2 Profiler PCR Array; Qiagen). Results were expressed as polymerase chain reaction (PCR) cycles to threshold and normalized to the average of 3 control genes, glyceraldehyde phosphate dehydrogenase (GAPDH), hypoxanthine phosphoribosyltransferase 1 (HPRT1) and β 2 -microglobulin (B2M). Secondary outcomes studied were 1-year mortality and long-term RV failure (RVF-LT). Results CCR3, CCR4, CCR6, CCR7 and CCR8 were downregulated in LVAD recipients with RVF. Within this cohort of patients, CCR4, CCR7 and CCR8 were further downregulated in those who required RV mechanical support. In addition, under-expression of CCR3 to CCR8 was independently associated with an increased risk of mortality at 1 year, even after adjusting for RVF. CCR expression did not predict RVF-LT in our patient cohort. Conclusions Pre-LVAD CCR downregulation is associated with RVF and increased mortality after implant. Inflammatory signatures may play a major role in prognostication in this patient population.

Rationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Methods: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Results: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p < 0.01). scPCP produced a significant deficit in NOR ( p < 0.05 vs. control) and no PFC dopamine increase was observed. Conclusions: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.

OBJECTIVE: To evaluate the association between maternal obesity and mood disorders including depression, anxiety, stress, and pregnancy-specific stress during pregnancy. STUDY DESIGN: This was a planned secondary analysis of a prospective cohort study investigating factors associated with preterm delivery. The cohort included women who initiated prenatal care before 20 weeks with a singleton pregnancy. Maternal mental health was assessed using four standard psychosocial behavioral measures to screen for depression, pregnancy-specific stress, anxiety, and stress. Screen positive scores for each tool were established based on previously published “high” scores. RESULTS: Of the 1010 women included in the cohort, 355 (35.1%) were obese. There was no significant difference in the number of obese women with stress (64.2% versus 68.4%, p = 0.18), pregnancy-specific stress (26.2% versus 22.1%, p = 0.15), or anxiety (38.6% versus 41.2%, p = 0.42); however, a greater number of obese women did report symptoms consistent with major depression when compared to women with BMIs

Objective Stress exposures may have a differential impact on risk and resilience for depression depending on their timing across development. We sought to determine whether adverse childhood experiences (ACEs) and their onset with respect to puberty contribute to the increased risk observed in first-episode major depressive disorder (MDD) during the menopause transition. Methods Participants were from the Penn Ovarian Aging Study cohort, which is composed of women from Philadelphia County, Pennsylvania, who underwent behavioral, cognitive, and endocrine evaluations approximately yearly from 1996 to 2012 and completed the Adverse Childhood Experiences Questionnaire at study end point (n = 243). ACEs that first occurred 2 or more years before menarche were considered prepubertal. Incident menopause MDD was defined as first observed onset of the disorder in the perimenopause to postmenopause transition using the Structured Clinical Interview for DSM-III-R and the Primary Care Evaluation of Mental Disorders. Results Incident menopause MDD occurred in 48% of the 100 women who reported lifetime MDD. Women reporting ≥ 2 total ACEs were at significantly greater risk for lifetime MDD (adjusted odds ratio [aOR] = 2.05, P = .034) and incident menopause MDD (aOR = 2.58, P = .03) compared to those reporting 0 ACEs; women with ≥ 2 postpubertal ACEs were 2.3 times more likely to experience incidence menopause MDD (P = .024) after controlling for race, smoking, body mass index, and employment. Experiencing only 1 ACE in the prepubertal window, regardless of additional ACEs in postpuberty, was associated with reduced risk for lifetime and incident menopause MDD. Conclusions Timing and number of adverse experiences with respect to puberty differentially impacted risk and resilience for MDD across the female life span and during the menopause transition in this community cohort.

Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Preclinical literature suggests latent effects of early life adversity on serotonin function may play a role in this phenomenon. However, evidence in human participants regarding the mechanisms by which loss of estradiol contributes to this vulnerability is lacking. Here we examined the impact of tryptophan depletion (TD) and adverse childhood experiences (ACE) on brain activation during a working memory task in menopausal women. We hypothesized that an interactive effect between ACE and TD would be observed when women were hypogonadal, and that treatment with estradiol would attenuate this effect. Thirty-three women underwent functional imaging at four time points (123 total scans) in this double-blind, placebo controlled, cross-over study. The effects of TD, ACE, and TD × ACE were evaluated using a voxel-wise, mixed-effects, 2 × 2 ANOVA. In the absence of exogenous estradiol, a TD by ACE interaction was observed on BOLD signal in the right DLPFC such that TD increased activation in high ACE subjects but decreased activation in low ACE subjects. While a similar interaction was observed with placebo treatment, treatment with estradiol attenuated the effects of ACE and TD such that no between or within group differences were observed. Together, these results suggest that early life adversity may have a lasting impact on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause.

Suffering related to dementia is multifaceted because cognitive and physical functioning slowly deteriorates. Advanced age and sex, two of the most prominent risk factors for dementia, are not modifiable. Lifestyle factors such as smoking, excessive alcohol use, and poor diet modulate susceptibility to dementia in both males and females. The degree to which the resulting health conditions (eg, obesity, type 2 diabetes, and cardiovascular disease) impact dementia risk varies by sex. Depending on the subtype of dementia, the ratio of male to female prevalence differs. For example, females are at greater risk of developing Alzheimer disease dementia, whereas males are at greater risk of developing vascular dementia. This review examines sex and gender differences in the development of dementia with the goal of highlighting factors that require further investigation. Considering sex as a biological variable in dementia research promises to advance our understanding of the pathophysiology and treatment of these conditions.

BackgroundKeratoacanthomas (KAs) are neoplasms of squamous epithelium which exhibit rapid growth and are often difficult to distinguish clinically from squamous cell carcinoma. Excision is the most common treatment, but in refractory cases or for KAs in cosmetically sensitive areas, nonoperative modalities may be better suited.ObjectiveTo compare efficacies of topical and intralesional therapies for the treatment of KAs.MethodsA systematic literature review was performed using Medline, Ovid, and Embase. Studies looking at the efficacy of topical or intralesional treatments for KAs were included. To compare efficacy, 2-tailed t-tests were performed, with P < .05 considered statistically significant.ResultsForty-one studies were identified across 5 modalities. Both topical and intralesional treatments had high KA eradication rates (92%-100%). Intralesional 5-fluorouracil led to faster KA healing times when compared to intralesional methotrexate (3.7 vs 4.6 weeks, P = .017). Similarly, topical 5-fluorouracil led to faster time to heal than topical imiquimod (3.8 vs 7.6 weeks with imiquimod, P < .0001).ConclusionFor nonoperative treatment of KAs, strong evidence currently exists for both topical and intralesional therapies. Decisions on which modality to use should be made on a case-by-case basis.

Background: Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for cognitive impairments associated with schizophrenia (CIAS). CIAS genetic risk factors may be more easily studied in mice; however, CIAS associated biomarker changes are relatively unstudied in the scPCP mouse. Aim: To characterize deficits in object recognition memory and synaptic markers in frontal cortex and hippocampus of the scPCP mouse. Methods: Female c57/bl6 mice received 10 daily injections of PCP (scPCP; 10 mg/kg, s.c.) or vehicle ( n = 8/group). Mice were tested for novel object recognition memory after either remaining in the arena (‘no distraction’) or being removed to a holding cage (‘distraction’) during the inter-trial interval. Expression changes for parvalbumin (PV), glutamic acid decarboxylase (GAD67), synaptosomal-associated protein 25 (SNAP-25) and postsynaptic density 95 (PDS95) were measured in frontal cortex, dorsal and ventral hippocampus. Results: scPCP mice showed object memory deficits when distracted by removal from the arena, where they treated previously experienced objects as novel at test. scPCP significantly reduced PV expression in all regions and lower PSD95 levels in frontal cortex and ventral hippocampus. Levels of GAD67 and SNAP-25 were unchanged. Conclusions: We show for the first time that scPCP mice: (a) can encode and retain object information, but that this memory is susceptible to distraction; (b) display amnesia after distraction; and (c) express reduced PV and PSD95 in frontal cortex and hippocampus. These data further support reductions in PV-dependent synaptic inhibition and NMDAR-dependent glutamatergic plasticity in CIAS and highlight the translational significance of the scPCP mouse.

Objective The impact of diabetes mellitus on the central nervous system is less widely studied than in the peripheral nervous system, but there is increasing evidence that it elevates the risk of developing cognitive deficits. The aim of this study was to characterize the impact of experimental diabetes on the proteome and metabolome of the hippocampus. We tested the hypothesis that the vitamin B6 isoform pyridoxamine is protective against functional and molecular changes in diabetes. Methods We tested recognition memory using the novel object recognition (NOR) test in streptozotocin (STZ)-induced diabetic, age-matched control, and pyridoxamine- or insulin-treated diabetic male Wistar rats. Comprehensive untargeted metabolomic and proteomic analyses, using gas chromatography-mass spectrometry and iTRAQ-enabled protein quantitation respectively, were utilized to characterize the molecular changes in the hippocampus in diabetes. Results We demonstrated diabetes-specific, long-term (but not short-term) recognition memory impairment and that this deficit was prevented by insulin or pyridoxamine treatment. Metabolomic analysis showed diabetes-associated changes in 13/82 identified metabolites including polyol pathway intermediates glucose (9.2-fold), fructose (4.9-fold) and sorbitol (5.2-fold). We identified and quantified 4807 hippocampal proteins; 806 were significantly altered in diabetes. Pathway analysis revealed significant alterations in cytoskeletal components associated with synaptic plasticity, glutamatergic signaling, oxidative stress, DNA damage and FXR/RXR activation pathways in the diabetic rat hippocampus. Conclusions Our data indicate a protective effect of pyridoxamine against diabetes-induced cognitive deficits, and our comprehensive ‘omics datasets provide insight into the pathogenesis of cognitive dysfunction enabling development of further mechanistic and therapeutic studies., Highlights • Pyridoxamine prevented long-term recognition memory deficits in diabetic rats. • Hippocampal protein changes are revealed by comprehensive untargeted proteomics. • Hippocampal metabolomic analysis showed increased polyol pathway intermediates. • Pyridoxamine altered synaptic plasticity-associated proteins in diabetic rats.

Background: Little research to date has focused on lower urinary tract symptom (LUTS) prevention and bladder health promotion in women. To address this gap, the Prevention of LUTS Research Consortium developed the following working bladder health definition: "A complete state of physical, mental, and social well-being related to bladder function [that] permits daily activities [and] allows optimal well-being." To begin to inform and quantify this definition, we used data from the Boston Area Community Health Survey, drawing upon its rare collection of information on LUTS and LUTS-specific interference with activities. Methods: At baseline, participants reported their frequency of 15 LUTS and interference with 7 activities. Prevalence ratios (PRs) were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. Results: Of the 3169 eligible participants, 17.5% reported no LUTS or interference, whereas the remaining 82.5% reported some frequency of LUTS/interference: 15.1% rarely; 21.7% a few times; 22.6% fairly often/usually; and 22.9% almost always. LUTS independently associated with interference were urgency incontinence, any incontinence, urgency, nocturia, perceived frequency, and urinating again after